Abstract

Cartilage destruction in the arthritides is thought to be mediated by two main enzyme
families: the matrix metalloproteinases (MMPs) are responsible for cartilage collagen
breakdown, and enzymes from the ADAMTS (a disintegrin and metalloproteinase domain
with thrombospondin motifs) family mediate cartilage aggrecan loss. Many genes subject
to transcriptional control are regulated, at least in part, by modifications to chromatin,
including acetylation of histones. The aim of this study was to examine the impact
of histone deacetylase (HDAC) inhibitors on the expression of metalloproteinase genes
in chondrocytes and to explore the potential of these inhibitors as chondroprotective
agents. The effects of HDAC inhibitors on cartilage degradation were assessed using
a bovine nasal cartilage explant assay. The expression and activity of metalloproteinases
was measured using real-time RT-PCR, western blot, gelatin zymography, and collagenase
activity assays using both SW1353 chondrosarcoma cells and primary human chondrocytes.
The HDAC inhibitors trichostatin A and sodium butyrate potently inhibit cartilage
degradation in an explant assay. These compounds decrease the level of collagenolytic
enzymes in explant-conditioned culture medium and also the activation of these enzymes.
In cell culture, these effects are explained by the ability of HDAC inhibitors to
block the induction of key MMPs (e.g. MMP-1 and MMP-13) by proinflammatory cytokines
at both the mRNA and protein levels. The induction of aggrecan-degrading enzymes (e.g.
ADAMTS4, ADAMTS5, and ADAMTS9) is also inhibited at the mRNA level. HDAC inhibitors may therefore be novel chondroprotective
therapeutic agents in arthritis by virtue of their ability to inhibit the expression
of destructive metalloproteinases by chondrocytes.